A. Technical Field
This invention relates to the synthesis of primary amines including optically active primary amines, and more particularly to improved processes for producing such primary amines from olefins and boronic esters, and to novel intermediates useful therein.
Optically active primary amines are of major biological and synthetic importance. For example, (R)-(-)-sec-butylamine is present in pharmacologically active species such as .beta.-blockers and CNS analgesics.
In the typical synthesis of primary amines, RNH.sub.2 from organoboranes, one organic group is typically lost as boronic acid which results in a maximum yield of 67% for less hindered R groups and 50% for more hindered R groups. Accordingly, there has been a long-standing need for methods which provide a more efficient transfer of organyl groups from boron to nitrogen. The present invention provides such intermediates and methodologies.
B. Prior Art
Organoboranes have been used to synthesize amines by reaction with appropriate aminating reagents such as NH.sub.2 Cl and NH.sub.2 OSO.sub.3 H (H. C. Brown, W. R. Heydkamp, E. Breuer, W. S. Murphy, J. Am. Chem, Soc, 1964, 86, 3365]; NH.sub.3 +NaOCl [G. W. Kabalka, K. A. Sastry, G. W. McCollum, H. Yoshioka, J. Org, Chem. 1981, 46, 4296); chloramine-T [V. B. Jigajinni, A. Pelter, K. Smith, Tetrahedron Letters 1978, 181] and Q-mesitylenesulfonylhydroxylamine (Y. Tamura, J. Minamikawa, S. Fujii, M. Ikeda, Synthesis 1973, 196].
As mentioned above, yields achieved in these prior art processes were, at most, 67% for less hindered R groups and 50% for more hindered R groups.
The reaction of trialkylboranes with freshly prepared chloramine proceeds in the presence of aqueous sodium hydroxide. However, only two of the three groups in R.sub.3 B were utilized. ##STR1## Consequently the maximum possible yield for R.sub.3 B is only 67%. H. C. Brown, W. R. Heydkamp, E. Breur and W. S. Murphy, J. Am. Chem, Soc., 86, 3365 (1964).
More hindered alkenes undergo hydroboration only to the dialkylborane stage, readily converted into the corresponding dialkylborinic acids or esters. These derivatives also react with preformed chloramine to form the primary amines. But in this case, only one of the two groups could be made to react. ##STR2## Consequently, in such cases, the maximum yield is only 50%. Moreover, the reaction of the more hindered dialkylborane derivatives is very sluggish with decreased yields. H. C. Brown, G. W. Kramer, A. B. Levy and M. M. Midland, "Organic Synthesis via Boranes", Wiley-Interscience, New York, 1975.
The preparation of optically active primary amines of very high enantiomeric purities from boronic esters of essentially 100% optical purity and LiMe was described by Herbert C. Brown et al, J. Am. Chem, Soc, 1986, 108, 6761-6764. This procedure produced optically pure primary amines in yields of between 72-83%. While improved yields were obtained on a laboratory scale, methyllithium is a relatively expensive reagent, and is too expensive to be used for large scale commercial production of amines. Thus a need remains for a process for economically producing primary amines in high yields as well as for economically producing optically active amines of high optical purity in improved yields.
The present invention provides a process which enables synthesis of both hindered and unhindered primary amines in excellent yields of up to 95%, and in all cases, in higher yields than those achieved by prior art methods.